The primary purpose of this pilot study is to determine whether African Americans (AA) with mild AD (AD) can be enrolled and retained in a 6-month aerobic exercise-training study. Using a randomized controlled trial approach, we will examine the effects of aerobic exercise-training on neurocognitive function, and on cerebral glucose homeostasis. It is yet to be determined whether AAs with mild AD can be recruited into such a study, nor has the relationship of fitness adaptation to neurocognitive function been systematically examined in this population. In addition to the goal of assessing the intervention effects, we will evaluate the differential relationships of APOE to aerobic fitness-induced changes in neurocognition. Our long-term goal is to explore the mechanism by which fitness adaptation exerts an effect on neurocognition -- Notably, low levels of high-density lipoprotein cholesterol (HDL-C), elevated inflammation (C-reactive protein (CRP) and interleukins (IL-1A)), deranged glucose homeostasis, hypertension and endothelia dysfunction are precursors of arteriolosclerosis, decreased cerebral perfusion and oxygen deprivation, all of which may increase AD risk. Because many of these putative AD risk factors are susceptible to lifestyle alterations, we will also assess their roles in aerobic fitness-related improvements in cognitive function and reduction in AD risk. A team of highly successful experts in neuroimaging, neurology, psychology, exercise physiology, cardiology and genetics has been assembled to conduct this study. After obtaining informed consent, participants will undergo initial exercise screening to determine their ability to exercise safely. Following randomization of 112 participants into intervention (n=56) and control (n=56) groups, baseline neuropsychological, neuroimaging and biomarker evaluations will be performed. The intervention group will undergo 3 times/week supervised aerobic exercise-training, while the control group undergoes stretch exercise 3 times/week. At the completion of a 6-month aerobic exercise-training by the intervention group, all baseline tests will be repeated in both the intervention and control groups. Between groups cognitive performance will be compared using appropriate multivariate methods. This proposed work has the potential to add a practical effective strategy to delay progression of AD in populations at most risk. Results consistent with our hypotheses will form the basis for large-scale clinical trials, and the prescription of aerobic fitness to prevent or attenuate the physical, psychological and the economic burden associated with AD. PUBLIC HEALTH RELEVANCE: The primary purpose of this pilot study is to determine whether African Americans (AA) with mild AD (AD) can be enrolled and retained in a 6-month aerobic exercise-training. Using a randomized controlled trial approach, we will examine the effects of aerobic exercise-training on neurocognitive function, and on cerebral glucose homeostasis. Preliminarily, we will evaluate the differential relationships of APOE polymorphism to aerobic fitness-induced changes in neurocognitive function. Our long-term goal is to examine the mechanisms by which fitness adaptation exert an effect on neurocognitive function. Although anticholinesterase therapies have greatly improved symptomatic treatment of AD, they have not been demonstrated to significantly slow disease progression. Excess morbidity and mortality from AD continue to generate an enormous economic burden on families and on the United States. Preservation of intellectual dexterity among those showing earliest symptoms of AD may ameliorate the physical, emotional, and economic burden associated with the disease, and that, is an important public health goal. A promising evidence-based and relatively side-effect free lifestyle approach is emerging as an alternative or adjunct to anticholinesterase therapy. Specifically, aerobic exercise-training has been demonstrated to improve cognitive function. Though, the effect size for these studies is surprisingly large, and the results fairly consistent, however, the sample sizes were small and included mostly Caucasians. Importantly, the mechanism by which an effect occurs is yet to be systematically substantiated. Remarkably, aerobic fitness can improve many of the putative AD risk factors such as high-density lipoprotein cholesterol (HDL-C), inflammation, and arteriolosclerosis. However, improvements in these putative risk factors have not been explored as potential mechanisms by which aerobic training improves cognitive function in humans. Given that AAs: i) have higher incidence and prevalence of AD than Caucasians, ii) have paucity of cross-sectional, and lack prospective data on the beneficial effect of exercise on cognitive function;iii) are more sedentary relative to Caucasians, in whom data show the beneficial effect of exercise, and therefore have room for exercise-induced improvements in risk;a randomized controlled trial of exercise and cognition in older AAs is imperative.